Patent GB-1335227-A (GB)
Title: Tetrahydrocarbazole carboxylic acids and esters and preparation thereof
Inventor: ALEXANDER E J
IPC: C07C243/38
Filed: 1971-06-01
Abstract: 1335227 Tetrahydrocarbazole-carboxylic acids STERLING DRUG Inc 1 June 1971 [2 June 1970] 18459/71 Heading C2C Novel compounds I in which (Ar) is a benzene or naphthalene ring; Q and Q 1  are 1-6C alkyl, phenyl-1-6C alkyl, 1-6C alkoxy, phenyl-1-6C alkoxy, phenoxy, phenyl, di(1-6C alkyl)amino, 1-6C alkanoylamino, trihalomethyl, CF 3 O-, halo or OH; Z and Z 1  are 1-6C alkylthio, 1-6C alkylsulphinyl, 1-6C alkylsulphonyl, NO 2  or amino; m is 0 to (3-n), p is 0 to (3-g); n and g are 0 or 1; R is H, 1-6C alkyl, 4-acetamidophenyl, (1-6C alkanoyloxy)methyl, or benzoyloxymethyl optionally substituted on the ring by one or two of 1-6C alkyl, 1-6C alkoxy or halo; and R 1  and R 2  are H or CH 3 , at least one being H; or (Q) m  with (Z) n  or (Q 1 ) p  with (Z 1 ) g  are methylenedioxy attached to adjacent carbon atoms and salts thereof are prepared by (1) reaction of compounds VI with compounds VII or with cyclohexanone-4,4-dicarboxylic acid to give compounds III which are then pyrolysed; (2) standard esterification of those compounds I in which R is H; (3) reaction of compounds VIII in which R is not H; Q 4  is 1-6C alkyl, phenyl- 1-6C alkyl, 1-6C alkoxy, phenyl-1-6C alkoxy, phenoxy, phenyl, di(1-6C alkyl)amino, trihalomethyl, CF 3 O- or halo; and Z 4  is 1-6C alkylthio; or (Q 4 ) m  with (Z 4 ) n  is methylenedioxy ; with compounds IX in which X is Br, Cl or F; Q 5  is as Q 4  and Z 5  is as Z 4 , (4) reaction of compounds IV in which R 5  is H; Q 6  is 1-6C alkyl or alkoxy, or halo; Z 6  is H; and r is 0-3 or Q 6  with Z 6  is methylene-dioxy; with compounds IX to give compounds IV in which R 5  is (Q 5 ) p (Z 5 ) g  Ar- CO- followed by hydrogenolysis. Novel compounds II in which Q 2  and Q 3  are 1-6C alkyl, phenyl- 1-6C alkyl, 1-6C alkoxy, phenyl-1-6C alkoxy, phenoxy, phenyl, di(1-6C alkyl)amino, trihalomethyl, CF 3 O-, halo or OH; Z 2  and Z 3  are 1-6C alkylthio; Ar, m, p, n and g are as defined above; R 3  is as R and R 4  is H or CH 3  or (Q 2 ) m  with (Z 2 ) n  or (Q 3 ) p  with (Z 3 ) g  are methylenedioxy attached to adjacent carbon atoms; and salts thereof are prepared by reaction of compounds X in which R 3  is not H with compounds IX or by reaction of compounds V in which R 5  is H with compounds IX to give compounds V in which R 5  is (Q 5 ) p (Z 5 ) g  Ar-CO- followed by hydrogenolysis. Benzaldehyde 1-benzoyl-1-(4-methoxyphenyl)- hydrazone is prepared by reaction of 4-methoxy phenylhydrazine with benzaldehyde, followed by reaction of the benzaldehyde 4-methoxyphenyl hydrazone with benzoyl chloride. Benzaldehyde 1-benzoyl-1-(2-fluorophenyl)-hydrazone is prepared similarly. Ethyl 6-bromocyclohexane-2-carboxylate (A) is prepared by bromination of ethyl cyclohexanone 2-carboxylate. 9 - Benzyl - 1,2,3,4 - tetrahydrocarbazole - 4- carboxylic acid is prepared by reaction of phenylbenzylamine with (A). This may be reacted with liquid NH 3  to give 1,2,3,4-tetrahydrocarbazole 4-carboxylic acid which may be reacted with benzyl chloride to give the benzyl ester. 9 - Benzyl - 6 - methoxy - 1,2,3,4 - tetrahydrocarbazole-4-carborylic acid is prepared by reaction of (4-methoxyphenyl)benzylamine with ethyl 6-bromocyclohexanone-2-carboxylate. 9 - (4 - Chlorobenzyl) - 6 - methoxy - 1,2,3,4- tetrahydrocarbazole-4-carboxylic acid is obtained by a similar method. 6 - Methoxy - 1,2,3,4 - tetrahydrocarbazole - 4- carboxylic acid is prepared by reaction of the 9- benzyl derivative with liquid NH 3 . The free acid may be converted by conventional methods to the benzyl ester. Acetaldehyde - 1 - benzoyl - 1 - (2 - bromophenyl)hydrazone is prepared by reaction of 2- bromophenyl hydrazine with CH 3 CHO followed by reaction with benzoyl chloride. Pharmaceutical compositions comprise a compound I or II together with a suitable carrier. They are administered orally or parenterally as anti-inflammatory agents.